Amino pryan ring derivative and composition and use thereof

Abstract

The present disclosure relates to an amino pyran ring derivative and a composition and use thereof, and in particular, to an amino pyran ring derivative represented by general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, a pharmaceutical composition comprising the derivative, and their medical use in the manufacture of a di-peptidyl peptidase IV (DPP-IV) inhibitor, in formula (I) the substituents are defined the same as those in the specification.

What is claimed is: 
     
       1. An amino pyran ring derivative represented by general formula (I) or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof: 
       
         
           
           
               
               
           
         
       
       wherein
 V is selected from the following groups: 
 
       
         
           
           
               
               
           
         
         Ar is a phenyl substituted with 0 to 5 R 1 ; 
         R 1  is selected from H, F, Cl, Br, I, hydroxyl, cyano, C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 2-8  alkynyl, —(CH 2 ) m —C 3-15  cycloalkyl, —(CH 2 ) m —(3- to 15-membered heterocycloalkyl), —(CH 2 ) m —C 6-10  aryl, —(CH 2 ) m —(6- to 10-membered heteroaryl), —(CH 2 ) m —C(═O)—R 5 , —(CH 2 ) m —NR 6 R 7 , —(CH 2 ) m —C(═O)—NR 6 R 7 , —(CH 2 ) m —O—C(═O)—NR 6 R 7 , —(CH 2 ) m —S(═O) n —R 8 , —(CH 2 ) m —NR 9 —S(═O) n —R 8 , —(CH 2 ) m —NR 9 —C(═O)—NR 6 R 7  or —(CH 2 ) m —NR 9 —C(═O)—R 5 , wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, —CH 2 F, —CHF 2 , —CF 3 , hydroxyl, C 1-4  alkyl or C 1-4  alkoxy, the heterocycloalkyl or heteroaryl has 1 to 5 atoms or groups selected from N, O or S(═O) n ; 
         R 2a  and R 2b  are each independently selected from H, F, Cl, Br, I, hydroxyl, cyano, C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 2-8  alkynyl, —(CH 2 ) m —C 3-15  cycloalkyl, —(CH 2 ) m —(3- to 15-membered heterocycloalkyl), —(CH 2 ) m —C 6-10  aryl, —(CH 2 ) m —(6- to 10-membered heteroaryl), —(CH 2 ) m —C(═O)—R 5 , —(CH 2 ) m —NR 6 R 7 , —(CH 2 ) m —C(═O)—NR 6 R 7 , —(CH 2 ) m —O—C(═O)—NR 6 R 7 , —(CH 2 ) n —R 8 , —(CH 2 ) m —NR 9 —S(═O) n —R 8 , —(CH 2 ) m —NR 9 —C(═O)—NR 6 R 7  or —(CH 2 ) m —NR 9 —C(═O)—R 5 , wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, I, —CH 2 F, —CHF 2 , —CF 3 , hydroxyl, C 1-4  alkyl or C 1-4  alkoxy, and the heterocycloalkyl or heteroaryl has 1 to 5 atoms or groups selected from N, O or S(═O) n ; 
         R 3a  and R 3b  are each independently selected from H, F, Cl, Br, I, hydroxyl, cyano or C 1-8  alkyl, wherein the alkyl is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, —CH 2 F, —CHF 2 , —CF 3 , hydroxyl, C 1-4  alkyl or C 1-4  alkoxy; 
         R 4a  and R 4b  are each independently selected from H, F, Cl, Br, I, hydroxyl, cyano or C 1-8  alkyl, wherein the alkyl is optionally further substituted with 0 to 5 substituents selected from F, Cl, Br, I, —CH 2 F, —CHF 2 , —CF 3 , hydroxyl, C 1-4  alkyl or C 1-4  alkoxy, and R 4a  and R 4b  are not at the same time H; 
         R 4  is selected from H, cyano, C 1-8  alkyl, C 1-8  alkoxy, C 2-8  alkenyl, C 2-8  alkynyl, —(CH 2 ) m —C 3-15  cycloalkyl, —(CH 2 ) m —(3- to 15-membered heterocycloalkyl), —(CH 2 ) m —C 6-10  aryl, —(CH 2 ) m -(6- to 10-membered heteroaryl), —(CH 2 ) m —C(═O)—R 5 , —(CH 2 ) m —NR 6 R 7 , —(CH 2 ) m —C(═O)—NR 6 R 7 , —(CH 2 ) m —O—C(═O)—NR 6 R 7 , —(CH 2 ) m —S(═O) n —R 8 , —(CH 2 ) m —NR 9 —S(═O) n —R 8 , —(CH 2 ) m —NR 9 —C(═O)—NR 6 R 7  or —(CH 2 ) m —NR 9 —C(═O)—R 5 , wherein the alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, I, —CH 2 F, —CHF 2 , —CF 3 , hydroxyl, C 1-4  alkyl or C 1-4  alkoxy, and the heterocycloalkyl or heteroaryl has 1 to 5 atoms or groups selected from N, O or S(═O) n ; 
         R 5  is selected from hydroxyl, C 1-8  alkyl, C 1-8  alkoxy, C 3-15  cycloalkyl, C 6-10  aryl, 6- to 10-membered heteroaryl, —O—C 3-15  cycloalkyl, —O—C 6-10  aryl or —O-(6- to 10-membered heteroaryl); 
         R 6 , R 7  and R 9  are each independently selected from H, C 1-8  alkyl, C 3-15  cycloalkyl, C 6-10  aryl, 6- to 10-membered heteroaryl or 3- to 15-membered heterocycloalkyl; 
         R 8  is selected from C 1-8  alkyl, C 3-15  cycloalkyl, C 6-10  aryl, 6- to 10-membered heteroaryl or 3- to 15-membered heterocycloalkyl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 0 to 5 fluorine atoms, and the heterocycloalkyl or heteroaryl has 1 to 5 atoms or groups selected from N, O or S(═O) n ; 
         m is selected from 0, 1 or 2; and 
         n is selected from 0, 1 or 2. 
       
     
     
       2. The amino pyran ring derivative represented by general formula (I) according to  claim 1 , or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein
 R 1  is selected from H or F; 
 R 2a  and R 2b  are each independently selected from H, C 1-6  alkyl, C 3-6  cycloalkyl or 3- to 8-membered heterocycloalkyl, wherein the alkyl, cycloalkyl or heterocycloalkyl is optionally further substituted with 0 to 3 substituents selected from F, Cl, Br, I, —CH 2 F, —CHF 2 , —CF 3 , hydroxyl, C 1-4  alkyl or C 1-4  alkoxy, and the heterocycloalkyl has 1 to 3 atoms or groups selected from N, O or S(═O) 2 ; 
 R 3a  and R 3b  are each independently selected from H or C 1-2  alkyl, wherein the alkyl is optionally further substituted with 0 to 3 substituents selected from F, hydroxyl or C 1-4  alkoxy; 
 R 4  is selected from H or —S(═O) 2 —R 8 ; 
 R 8  is selected from C 1-6  alkyl, C 3-6  cycloalkyl, C 6-10  aryl, 6- to 10-membered heteroaryl or 3- to 8-membered heterocycloalkyl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl is optionally further substituted with 0 to 5 fluorine atoms, the heterocycloalkyl or heteroaryl has 1 to 5 atoms or groups selected from N, O or S(═O) 2 . 
 
     
     
       3. The amino pyran ring derivative represented by general formula (I) according to  claim 2 , or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein
 V is selected from: 
 
       
         
           
           
               
               
           
         
         Ar is selected from 2,5-difluorophenyl or 2,4,5-trifluorophenyl; 
         R 2a  is selected from H, C 1-6  alkyl, or C 3-6  cycloalkyl, wherein the alkyl or cycloalkyl is optionally further substituted with 0 to 3 substituents selected from F, hydroxyl, C 1-4  alkyl or C 1-4  alkoxy; 
         R 1a  and R 1b  are each independently selected from H or C 1-2  alkyl, wherein the alkyl is optionally further substituted with 0 to 3 substituents selected from F, hydroxyl or C 1-4  alkoxy; 
         R 4  is —S(═O) 2 —R 8 ; 
         R 8  is selected from C 1-2  alkyl, 3- to 6-membered heterocycloalkyl, or C 3-6  cycloalkyl; 
         wherein the alkyl, heterocycloalkyl, or cycloalkyl is optionally further substituted with 0 to 5 fluorine atoms, and the heterocycloalkyl has 1 to 3 atoms or groups selected from N, O or S(═O) 2 . 
       
     
     
       4. The amino pyran ring derivative represented by general formula (I) according to  claim 3 , or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein
 V is 
 
       
         
           
           
               
               
           
         
       
     
     
       5. The amino pyran ring derivative represented by general formula (I) according to  claim 4 , or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein
 R 4  is —S(═O) 2 —R 8 ; 
 R 8  is selected from C 1-2  alkyl,  4 - to  6 -membered heterocycloalkyl , or C 3 - 6  cycloalkyl; 
 wherein the alkyl, heterocycloalkyl , or cycloalkyl is optionally further substituted with 0 to 5 fluorine atoms, and the heterocycloalkyl has 1 to 3 atoms or groups selected from N, O or S(═O) 2 . 
 
     
     
       6. The amino pyran ring derivative represented by general formula (I) according to  claim 5 , or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein R 8  is selected from methyl, ethyl, 
       
         
           
           
               
               
           
         
       
       cyclopropyl, cyclobutyl, or cyclopentyl. 
     
     
       7. The amino pyran ring derivative represented by general formula (I) according to  claim 1 , or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the amino pyran ring derivative is selected from: 
       
         
           
           
               
               
           
         
       
     
     
       8. The amino pyran ring derivative represented by general formula (I) according to  claim 7 , or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the amino pyran ring derivative is selected from: 
       
         
           
           
               
               
           
         
       
     
     
       9. The amino pyran ring derivative represented by general formula (I) according to  claim 8 , or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the amino pyran ring derivative is selected from: 
       
         
           
           
               
               
           
         
       
     
     
       10. The amino pyran ring derivative represented by general formula (I) according to  claim 1 , or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the amino pyran ring derivative is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       11. The amino pyran ring derivative represented by general formula (I) according to  claim 10 , or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, wherein the amino pyran ring derivative is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       12. A pharmaceutical composition, comprising: an effective amount of the amino pyran ring derivative represented by general formula (I) according to  claim 1  or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof; and a pharmaceutically acceptable carrier or excipient. 
     
     
       13. Use of the amino pyran ring derivative represented by general formula (I) according to  claim 1  or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutical composition comprising: an effective amount of the amino pyran ring derivative represented by general formula (I) according to  claim 1  or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof; and a pharmaceutically acceptable carrier or excipient, in the manufacture of a di-peptidyl peptidase IV inhibitor. 
     
     
       14. The use according to  claim 13 , wherein the di-peptidyl peptidase IV inhibitor is used to manufacture a medicament for treating a metabolic disease, wherein the metabolic disease includes diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinism, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X-syndrome, diabetic complications, atherosclerosis, or hypertension. 
     
     
       15. The use according to  claim 14 , wherein the diabetes is type II diabetes. 
     
     
       16. A method for treating a metabolic disease, comprising:
 administering an amino pyran ring derivative represented by general formula (I) according to  claim 1  or a stereoisomer, a pharmaceutically acceptable salt, or a prodrug thereof; or a pharmaceutical composition comprising: an effective amount of the amino pyran ring derivative represented by general formula (I) according to  claim 1  or a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof; and a pharmaceutically acceptable carrier or excipient. 
 
     
     
       17. The method according to  claim 16 , wherein the metabolic disease includes diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, insulin resistance, hyperglycemia, hyperinsulinism, elevated levels of fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, X-syndrome, diabetic complications, atherosclerosis, or hypertension. 
     
     
       18. The method according to  claim 17 , wherein the diabetes is type II diabetes.